A critical event that activates caspases and induces apoptosis in mammalian cells is the release of cytochrome c from the mitochondria into the cytosol. However, our preliminary data indicate that while endogenous release of cytochrome c can readily induce apoptosis in mitotic cells, it is not sufficient to do so in sympathetic neurons. In addition, we find levels of cytochrome c protein, but interestingly not levels of cytochrome c mRNA, to be strikingly low in neurons as compared to mitotic fibroblasts. Our hypothesis is that a sympathetic neuron's resistance to the endogenous release of cytochrome c is due to low levels of cytochrome c in neurons. The aims of this proposal are: 1) to examine whether cytochrome c levels are limiting for apoptosis in neurons, and determine if they increase in response to apoptotic stimuli. 2) to test the hypothesis that SM-20 (which is induced in apoptotic neurons) is to increase cytochrome c levels to permit apoptosis in neurons. 3) to ask whether the differential expression of cytochrome c seen in mitotic cells and postmitotic neurons is a result of decreased translation or increased protein turnover in sympathetic neurons. [unreadable] [unreadable]